Cannabinoids have been shown to produce analgesia in rodents, monkeys and humans. However, males and females may be differentially sensitive to cannabinoids. For example, perinatal exposure to the cannabinoid delta-9-THC alters midbrain opioid receptor binding and opioid analgesia differentially in female vs. male rats. Sex differences have been found in midbrain cannabinoid receptor density and liver metabolism of cannabinoids, which may contribute to sex differences in the behavioral effects of cannabinoids. Because cannabinoids may provide a significant alternative analgesic pharmacotherapy to opioids -- and in fact are already being used for their anti-nausea and appetite stimulation effects -- it is important to determine whether these substances are equi-effective in men and women. The goal of the proposed research is to compare cannabinoid-induced antinociception in male vs. female rats. The first aim is to determine the potency and time course of cannabinoid-induced antinociception and sedation. Three agonists will be examined: the major psychoactive compound in marijuana, delta-9-THC; the major active metabolite of delta-9-THC,11- hydroxy-delta-9-THC; and the synthetic cannabinoid, CP55,940. Complete dose- and time-effect curves will be obtained for each agonist administered i.p. on the warm water tail withdrawal, paw pressure and spontaneous locomotor activity tests. The second aim is to compare supraspinal vs. spinal CB1 receptor mediation of cannabinoid effects in males and females. Complete dose- and time-effect curves will be obtained for antagonism of i.p. CP55,940 by the CB1 receptor-selective antagonist SR141716A administered i.c.v. and i.t..